Oakes began the talk by explaining what epigenetics is: heritable information not encoded in the DNA sequence (A/T/C/G). Epigenetic states are programmed in cell lineage development and become fixed in mature, differentiated cells defining their cellular identity. Cancer cells acquire aberrant epigenetic marks that are key to a malignant phenotype.

Where do the different epigenetic patterns in CLL come from?

CLL subgroup-specific methylation states are mirrored in normal B-cell subsets. A huge amount of DNA methylation takes place during maturation of B-cells and DNA methylation programming is associated with numerous annotated pathways:

Members of the BCR signaling pathway

8.62

Genes related to PIP3 signaling in B-lymphocytes

6.21

Chronic Myeloid Leukemia

5.95

Gene regulation by peroxisome proliferators via PPARα

5.93

B-Cell Antigen Receptor

5.56

Trefoil Factors initiate mucosal healing

4.96

Role of Erk5 in neuronal survival

4.92

B-Cell survival pathway

4.91

A large proportion of the epigenetic patterns observed in CLL derives from the epigenetic status of the founder cell.

Overall, in CLL, the majority of methylation marks relate to normal B-cell maturation. Moreover, CLL methylation pattern is closer to memory than naïve B-cells. However, LP-CLL selectively maintain naïve B-cell states at specific genes. Lastly, the epitype derives from the maturation state of the cell of origin.